YINSIDE: MEETING THEWORLD'S CHALLENGE |
`The Healthy Living Magazine of the American Diabetes Association for More Than 50 Years
`
`NOVEMBER 2007
`
`Pumpkin
`Pecan Cake
`
`-PAGE.70
`One of a dozen
`ee ireeaa)
`A recipes inside! /
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`J
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`_A special guide to entertaining
`for a happy, healthyholiday Sorel
`‘with menu ideas from Asia,Italy, and America®
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`DEXCOM
`EXHIBIT 1037
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`41 I Where We Stand Almost 6 percent of the world's population
`has diabetes: 246 _million people. And that number is growing. We mark the
`first World Di_abetes Day, November 14, with a look at the global crisis.
`48 I Powder Days Skier Jim Stokes isn't letting vision problems keep
`him from conquering the slopes. BY KATE RUDER
`94 I Diabet_es Advisor Is it your job that's putting on the pounds?
`Plus: How a physical therapist can help with arthritis paif!; and the best way
`to beat insomnia. BY SHAUNA s. ROBERTS, PHD
`
`Volume (jiO Number 12·
`
`On:Ib_~o..ve.~t ~---(cid:173)
`celebrate ' pag~ 51 I
`On_,The Slo,p.es,page·4~"1',
`PJfl,splihing: i>~g~.2~ 1
`World's Challenge-page 41 I
`
`[ S p E C I A L S. E C .T I O N ]
`Time to celebrate, with delicious recipes
`that will help you stay on target.
`72
`82
`
`52
`
`An Asian
`Evening
`
`62
`
`The American
`Revolution
`
`Brunch,
`Italian Style
`'
`
`A little help in. the
`holiday kitchen
`
`m. -
`
`--- -_
`-
`~ <;;~v~r pl'loto!!}r;tr;i"1 -by
`Taran %;-foocil ~tylingby
`Sl!!Zcilillile Sprin§er and(cid:173)
`Sysan Bond Por~~m_af'.l,
`
`MORE ►
`
`Advertisers On!in e To get additional information and free offers from advertisers in this issue, visit diabetes.org/forecastads.
`
`DIABETES FORECAST
`
`j NOVEMBER 2007
`
`

`

`epartments
`
`9 I Guest Editorial ~,,
`China1s Pr'.oblerh$ ..
`the World's Chal1enge
`By Henry Rodriguez, MD
`10 I Mail Call
`16 I Ask the Experts
`21 I Research Shorts
`The b~nefits of 'pill splitting; newer
`drugs are hot necessarily better;
`fiber and gestational diabetes risk;
`kids, pumps, and lows during
`exercise; cystic fibrosis; children's
`skin problems.
`37 I Recipe Cards Rainbow Rice;
`Home Fries; Gold Grit's; Orzo Pasta.
`
`(
`
`85 I Diabetes Advocate
`Representatives Mike Castle (R-DE)
`and Zack Space (D-OH) live a day
`in the life of someone with diabetes.
`88 I ADA Research Profile
`Kidney transplantation is a
`tricky business. Kathie
`Lynn Hermayer, MD, MS ,
`believes tight blood glucose
`control can improve the
`chances of success.
`104 I Shopper's Guide .
`116 I Reflections One
`teacher finds the strength to
`share that he has diabetes(cid:173)
`in front of his entire school.
`
`PRAC-TICAL
`LIVING-..
`3'2 I A trimRler You,
`Hi')w not tp l~t ti,blg holidays
`wetgh you>d('.)W:Fl.
`34 I ~ 'ir.1d:Matt~rs
`Is it time to i!,clcl massage
`-tbJ.erapy to -yoµi,(cid:173)
`treatment regir.rnm?
`
`-92 I, News Ygu C~n(cid:173)
`Use Get a sneak peek
`at ADA's· Sfg Book
`.Of JJiabetic Desserts.
`And fu'oll!e :your fo0d(cid:173)
`fact skiHs wiH1 t:he
`Associati@n's' new
`'
`'
`Diabe,tesB@0clSmart
`free e.-newsletter.
`
`,
`
`DIABETES FORECAST" is a registered trademark of the American Diabetes_ Assoc_iation-all rig_hts reserved,
`DIABETES FORECAST (ISSN 0095-8301) is published monthly by _the American _Diabetes AssocIatIo_n: 1701 N,_ Beaureflard
`St, Alexandria, VA 22311, 1-800-806-7801. Periodicals postage paid at Alexandria, Vrrgrn1a, an? add1t1onal ma_1lrng offices,
`POSTMASTER: Send change of address to DIABETES FORECAST, American Diabetes AssocIat1on, Membership Center,
`P,O, Box 444, Mount Morris, IL 61054-0444, U,S, membership dues are $28 per year (Canada, $68; Mexico, $68; all ot~er
`couritries,'$98), $21 of which is designated for DIABETES FORECAST, Back issues: $4 plu_s $5 for postage and handling
`to the U.S., $4 plus $13 for postage and handling to Canada and Mexico; all other countqes, $4 plus $16 for posta~e and
`handling, ©American Di~betes Association, 2007, All rights reserved under lnterna_t1onal and _Pa_n-American Coi:iyright
`Convention, This magazine may not be reproduced rn whole or rn part w ithout written permIssIon of the America~
`Diabetes Association, The American Diabetes Association is a nonprofit organization. All donations are tax deductible,
`
`DIABETES FORECAST I NOVEMBER 2007
`
`

`

`Lee Sanders, DPM
`Chief, Podiatry Servi<;e
`VA Medical Center
`Lebanon, Pa.
`
`Evan M. Sisson, PharmD, MHA, CDE
`Clinical Pharmacy Manager
`Southside Regional Medical Center
`Petersburg, Va.
`
`Lt. Col. Nina Watson, RN, BSN, CDE
`Endocrinology Flight Commander
`Wilford Hall Medical Center
`Lackland AFB, Texas
`
`Michael A. Weiss, Esq.
`Attorney
`. Keevican Weiss Bauerle &
`Hirsch LLC
`Pittsburgh, Pa.
`
`Chair, Advertising
`Review Panel
`Gregg F. Gerety, MD
`
`November 2007 Volume 60 Number 12
`
`I Editor-In-Chief I
`Paris Roach, MD
`Associate Professor of Clinical Medicine
`Division of Endocrinology and Metabolism •
`Indiana University School of Medicine.
`Indianapolis, Ind.
`
`I Associate Editors I
`
`David Marrero, PhD
`J_O. Ritchey Professor of Medicine
`Division of Endocrinology and Metabolism
`Indiana University School of Medicine
`Indianapolis, Ind.
`
`Christy L. Parkin, MSN, RN, CDE
`Health Management Resources, Inc.
`Diabetes Education and Consulting Services
`Carmel, Ind.
`
`Sue Robbins, RD, CDE
`Diabetes Dietitian
`Clarian Health
`Indiana University Diabetes Center
`Indianapolis, Ind.
`
`Henry Rodriguez, MD
`Associate Professor of Pediatrics
`Division of Pediatric Endocrinology and
`Metabolism
`Indiana University School of Medicine
`Indianapolis, Ind.
`Robyn Webb, MS, LN
`President, Robyn Webb Associates
`Alexandria, Va.
`
`·
`
`Craig Williams, PharmD
`Associate Professor of Pharmacy
`Oregon Health and Science University
`Medical Center
`Oregon State University College of
`Pharmacy
`Portland, Ore.
`
`j Editorial Board J
`Roger P. Austin, MS, RPh, CDE
`Clinical Pharmacy Specialist
`Henry Ford Health System
`Detroit, Mich.
`
`Paul Ciechanowski, MD, MPH
`Associate Professor
`Consultation-Liaison & Primary Care
`Psychiatry
`University of Washington
`Seattle, Wash.
`
`Belinda Childs, MN, ARNP, BC~ADM, CDE
`Clinical Nurse Specialist
`Mid-America Diabetes Associates
`Wichita, Kans.
`
`Robert A. Gabbay, MD, PhD
`Executive Director, Penn State Diabetes and
`Obesity Institute
`Associate Professor of Medicine
`Penn State College of Medicine
`Hershey, Pa.
`
`.Bret Goodpaster, PhD
`Assistant Professor of Medicine
`Director, Ex~rcise Physiology Laboratory,
`Obesity Nutrition Research Center
`University of Pittsburgh
`Pittsburgh, Pa.
`
`Janis McWilliams, RN, MSN, CDE,
`-BC-ADM
`Advanced Practice Diabetes Specialist
`University of Pittsburgh
`Medical Center
`University of Pittsburgh
`Diabetes Institute
`Pittsburgh, Pa.
`
`American Diabetes Associ~tion.Officers
`thiAIR OF THE BOAR0
`CHAIR OF :JJIE BOARD-ELECT<
`R. Stewart Perry
`Darlene L. Cain
`'
`P.RESIDEN:r, MEDICINE & SCIENCE
`. SECRET~RY /rREASURER,,ELlECT
`Rp bert C. Garr~tt, FACl:iE .
`John B. Buse, MO, PhD
`PRESIDENT, HE.A:LTH CARE &,EDUCATION
`v,1e·E Cl:IAIR OF liHE·BOARD
`0egrge J. Huntley, CPA
`Ann ~' Albri~ht; PnD, RP
`.
`SECRETARY /TREASURER'
`Vl~E PRESIDENT, MEDICINE & SCIENCE
`George W. Booker, II, CPA
`R. Paul Robertson, MD
`-
`
`VICE PRESIDENT, H'EAtTH C}\RE &-El.')UCNriON
`-
`Susan M.c~aughli~, BS, ijQ, COE
`VltE .S~CRETARY./TREASURER
`T. Edwin Stinson, Jr_
`CHIEF EXECUTIVE OFFICER
`Larry-Hausner-
`
`D I A B E T E S F O R E C A S T
`
`1• N O V E M B E R 2 0 0 7
`
`

`

`rec [
`
`November 2007 Volume 60 Number 12
`
`MARTHA RAMSEY
`
`Vice President,
`Publications
`
`SARA SKLAROFF
`
`Editorial Director
`
`ANDREW KEEGAN
`
`Director,
`Consumer Publications
`
`JOHN C. WARREN
`
`Managing Editor
`
`KATIE BUNKER
`
`Departments Editor
`
`THE MAGAZINE GROUP Design & Layout
`
`HOWARD RICHMAN Associate Publisher
`
`LISA DIGGS
`
`Advertising
`Production Specialist
`
`Director,
`JAMES SKOWRENSKI
`Membership/Subscription Services
`
`CARYN-COCHRAN
`
`Associate Pirector,
`Fulfillment
`
`Manager,
`. JEREMY N. BAIRD
`Membership/Subscription Servi_ces
`
`JOHN KLEMICK
`
`Director, Financial
`Operations, Publications
`
`LAURIE ANN HALL
`
`Associate Director,
`Billing & Collections,
`Publications
`
`I Our Mission I
`
`The Mission of the American Diabetes
`Association is to prevent and cure diabetes
`and to improve the lives of all people
`affected by diabetes.
`■ The American . Diabetes Association
`recommends that all people with diabetes
`be educated health care consumers.
`We encourage you to read labels, ask
`ques.tions, and be an active participant
`in your own health care.
`■ The American Diabetes Association
`recommends that consumers familiarize
`themselves with nutritional information
`about food products.
`
`Advertisements contained in Diabetes
`Forecast are reviewed by the Advertising
`Review Panel according to established
`criteria and guidelines. The objective is to
`support public awareness of commercially
`available products and to. avoid advertisements
`that might deceive or mislead the reader.
`Acceptance of advertisements in Diabetes
`Forecast should not be construed, however,
`as an endorsement by the American Diabetes
`Association. The committee does not test
`advertised products and, therefore, cannot
`ensure their safety and efficacy. Companies
`selling through the mail must comply with
`federal regulation·s regarding customer
`notification if the product is not available
`within 30 days. Acceptance of advertising
`does not imply that the American Diabetes
`Association has conducted an independent
`scientific review to validate product safety and
`efficacy or advertising claims. The Association
`reserves the right to reject any advertisement
`for any reason, which need not be disclosed
`to the party submitting the advertisement.
`
`awar:ds
`Ass0ciation Trencls Gold Awarcl .for
`Pr0fessi0nal1 SoEiety··Mai;Jazine
`·
`Tlie So<siety of National Association
`Publications (SNAP) Excel Awards for
`Excellence in Asso.ciati0n Publish'ing for
`Single~Topic Issue, and' a Silver -Award•
`for Mggazines: G~Freral Exeellence
`.(omm1micati9n Concept's Apex Awards for
`Publicatic;m ~xcellenGe and Feature Writing
`Ne0graphics Award:for Outstanding Qcra!jt.y
`and Graft'smamsf;iipi ir.i the.Art·of Grapnic
`Repr0du;:ti0n
`
`A:meriear.i Society· 0f Associatior'l' Execotives
`(ASAE)•Certific:ate 0f-Adii~vernent
`American Motore;ydist Association Most
`li'aluep P.uolicati0n Aw~rd·
`Certifit ate of Qesign Excell·er.1<1e,
`'P.rint's R~gi0nal'.Desii;Jm·· Annual
`Art l:>irect0r-s €1ub 0f l'v1etropio[ital') Washington,
`numer_ous awards inc:luein_g '1Best Of..:' categor.y
`Silver Award for'"BestTable .0f fontents:'
`Ass0dation/Nqppr0fit, Folio: Ozzie Awares for
`Magazir.ie Desi~r,i Exc;ellen-ee.
`
`I Advertising Sales Offices I
`Consumer Northeast/Southeast
`Noel White, Karen Kolar
`Noel White & Asscrciates, Inc.
`P.O. Box 285
`Denver, NY 12421
`(845) 254-6725
`
`Consumer Midwest
`Kevin Zoeller, Whitney Deluca
`Zoeller Media Sales
`35 East Wacker Drive, Suite 1080
`Chicago, IL 60601
`(312) 782-8855
`
`Pharmaceutical/Medical
`B. J,oseph JacJ.cson, Chc:\fles Novak,
`Paul Nalbandi_an
`Thi', Jackson-Gaeta Group, {nc.
`33 Smull Avenue
`Caldwell, NJ 07006
`(973) 403-7677
`
`Shopper's Guide ·
`Denice Moultrie
`American Diabetes Association
`1701 N . Beauregard Street
`Alexandria, VA 22311
`(703) 549-1500 ext. . 1329
`
`Membership/Address Changes
`For membership inquiries· and address
`changes, please contact our Diabetef
`Forecast customer service center at
`1-800-806~7801.
`
`Opinions expressed in signed articles are _those
`of the authors and are not necessarily endorsed
`by the American Diabetes Association®, Inc.
`
`Printed in U.S.A.
`
`To reach the American Diabetes Association,
`call 1-800-342-2383.
`
`.Ll. '"""""""" ~w
`
`DI A BETE S FOREC AST I NOVEMBER 2007
`
`

`

`[ mail call ]
`
`Thanks, Lt. Col. Watson
`I want to thank you for your
`Guest Editorial about U.S. Air
`Force (USAF) doctors and
`nurses, and Lt. Col. Nina
`Watson in particular, in your ·
`August issue (p. 9). I have
`been a military dependent all
`of my life, first of my father,
`who retired from the Army,
`and then my husband, who
`retired from the Air Force
`in 2005. The majority of my
`medical care for type 1
`diabetes, which I've had for
`23 years, and other issues has
`been administered by the
`USAF medical. system. I have
`seen many doctors in many
`places around the world, and
`they do an excellent job. They
`cannot be commended
`enough.
`In 2000, when we were
`stationed at Keesler Air Force
`Base in Biloxi, Miss., I was
`seen by Lt. Col. (then Maj.)
`Watson. She was instrumental
`in getting me an insulin pump
`and worked many hours with
`me, makirig sure that I knew
`how to use the pump and got
`the most benefit out of it.
`Because of that pump I was
`able to have a little girl in
`May 2001. My pregnancy was
`a lot of work, but not nearly
`as much as it would have been
`without the pump. My AlC
`stayed down around 5.8 for
`the duration of my pregnancy,
`and my daughter was born
`with no complications.
`
`Thank you, Lt. Col. Watson,
`for your dedication and work
`for so many people with dia(cid:173)
`betes. Good luck on your de(cid:173)
`ployment and stay safe!
`JoAnne Beall
`Columbus, Miss.
`
`Rock of Love
`I am a 38-year-old female
`with type 2 diabetes and an
`avid reader of Diabetes fore(cid:173)
`cast. I wanted to let you know
`how excited I was to see Bret
`Michaels on the cover of your
`August issue. I have always
`liked him and his group,
`Poison. I really enjoyed
`reading the article about him
`and found it inspirational.. If
`he can take four shots a day
`and , check his glucose six to
`10 times a day, I can improve
`my diet and exercise. After
`all, I am not even insulin(cid:173)
`dependent, and don't have
`anywhere near the busy
`schedule that he does!
`
`I also found it interesting
`that he struggles with food
`choices, as I do. My favorite
`part of the article was when
`he said, "You're occasionally
`allowed to throw a tantrum,
`but you have to keep your
`humor about it. Humor is es(cid:173)
`sential to winning at diabetes."
`Lori Schettler
`Salt Lake City, Utah
`
`Byetta Fan
`In the August Mail Call,
`Hillary S. Liber asked why
`you did not mention Byetta
`and Symlin in your May arti(cid:173)
`cle about 1nsulin and weight
`gain ("A Matter of Balanc~:
`Insulin And Weight Gain,"
`p. 16). I too have been look(cid:173)
`ing for articles about Byetta.
`Thankfully, while I was
`spending a winter in Austin,
`
`continued on page 13
`
`mail call
`Sen(:l letters to Mail Call,
`Diabetes Forecast,. 1701 North
`Beauregard St., Alexandria, VA
`22311. You can also send
`e-mail messages to mailcall@
`diabetes.org. Because of the
`large volume of mail we
`receive, we are not able to
`publish all letters and reserve ·
`the right to edit for length.
`Although we will honor
`requests for anonymity, all
`letters to Diabetes Forecast
`must include your full name
`and home address.
`
`DIABETES FORECAST I NOVEMBER 2007
`
`

`

`" " ~,
`ler
`ah
`
`l-
`
`13
`
`You can help protect against the· formation of clots and
`reduce your risk of a future heart attack or stroke.
`
`This is important information if you've been
`hospitalized with heart-related chest pain or had
`a heart attack. That's ,b~cause these conditions; known as
`Acute Coronary Syndrome-or ACS-are usually caused w.hen
`blood platelets stick together and form clots that block blood
`flow to your heart. And if you've already had a clot, you're at an
`increased risk for a future heart
`attack or stroke.
`
`PLAVIX, taken with other
`heart medicines, helps
`provide greater protection
`against heart attack or
`stroke than other heart
`medicines alone. That's because prescription PLAVIX
`works differently than your cholesterol and blood pressure
`medications, focusing on your blood platelets to help keep them
`from sticking together and forming clots.
`
`If you need help paying for prescription medicines,- 1 ,/ Ib. .
`\_•A/ , Partner;hip for
`you may be eligible for assistance. Call 1-888-4PPA-N0W
`(1-888-477-2669),or go to www.pparx.org
`.~ . · Prescription Assistance
`
`-
`
`© 2007 Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership
`
`IMPORTANT INFORMATION: If you have a stomach
`ulcer · or other condition that causes bleeding, your~
`should not use PLAVIX. When taking PLAVIX alone or
`with some other medicines including aspirin, the risk
`of bleeding may increase so tell your doctor _ before
`planning surgery. And, always talk to your doctor
`before taking aspirin or other medicines with PLAVIX,
`especially if you've had a stroke. If you develop fever,
`unexplained weakness or confusion'. tell yo1:1r doctor
`promptly as these may be signs of ·a rare but
`potentially life-threatening condition called TTP,·
`which has been reported rarely, sometimes in less than
`_2 weeks after starting therapy. Other rare but serious
`side effec_ts may occur.
`See important prodL!ct information
`on the_ following page.
`
`ONCE-A-DAV Plavix®
`
`(clopidogrel bi sulfate) 75mg tablets
`Help stop a clot before a clot stops you.
`
`To learn more, talk to your doctor today. _
`Or visit www.plavix.com or call 1.877 .897 .5682
`
`-~_anofi event~!;. ~ Bristol-Myers Squibb
`US.CLO.07.07.080/September 2007 264US07AB35508-09-07
`sanoli-aventis U.S. LLC
`
`

`

`Rx only
`
`PLAVIX®
`clopidogrel bisullate tablets
`INDICATIONS AND USAGE
`PLAVIX (dopidogrel bisulfale) is indicated for the reduction of atherothrombotr'c events as
`follows·
`• Recent Ml, Recent Stroke or Establish~ Peripheral Arterial Disease
`fof palients wilh a history of recent myocardial infarction (Ml). recent stroke, or established
`peripheral arterial disease, PlAVIX has been shown to rtduce the rate of a combined end•
`poinl of new ischemic stroke (fatal or not), new Ml {fatal or not), and other vascular death.
`• Acute Coronary Syndrome
`-For patients with non-ST-segment elevation acute coronary syndrome (unstable
`angina/non-Q-wave Ml) including patients who are to be managed medilally and those
`who are to be managed with percutaneous coronary intervention (with or without stenl}
`or CABG, PLAVIX has been shown to decrease the rate of a combined endpoint of cardio(cid:173)
`vascular death, Ml, or stroke as well as the rate of a combined endpoint of cardiovascular
`death, Ml, stroke, or refractory ischemia
`-For palienls wilh ST•sesmenl elevatMJn acute myocardial infarction, Pl.AVIX has been
`shown to reduce the rate of death from any cause and the rate of a combined endpoint of
`death, re-infarction or stroke. This benefit is not known to pertain to patients who receive
`primary angioplasty.
`CONTRAINDICATIONS
`The use of PLAVIX is contraindicated in the following conditions.
`Hypersensitivitytothedrugsubstanceoranycomponentoftheproduct.
`Active pathological bleeding such as peptic uk~r or intracranial hemorrhage.
`WARNINGS
`.
`Thrombotic thromboqtopenic purpura fTTP):
`TTP has been reported rarely following use of PLAVIX, sometimes after a short exposure
`(<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment
`including plasmapheresis (plasma exchange) II is characterized by thrombocytopenia,
`microangiopathic hemofytic anemia (sch;stocytes (fragmented R8Cs) seen on pe1ipheral
`smear), neurological findings, renal dysfunction, and fever. (See ADVERSE REA.OIONS.)
`PRECAUTIONS
`General
`PlAVIX prolongs the bleeding lime and therefore should be used with caution in patients
`who may be at risk of increased bleeding from trauma, ~urgery, or other pathological
`conditions (particularly gastrointestinal and intraocular). If a patient iS to undergo elective
`surgery and anantiplateleteffect is not desired, PLAVIXshould be discontinued 5daysprior
`to surgery.
`Due to the risk of bleeding and undesirable hemalofogical effects, blood cell count determi(cid:173)
`nation and/or other appropriate testing should be promptly considered, whenever such
`suspected clinical symptoms arise during the course of treatment (see ADVERSE REACTIONS).
`In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the
`combination of aspirin and PlAVlX has nol been shown to be more effective than
`PLAVlX alone, but the combination has been shown to increase major bleeding.
`GI Bleeding: In CAPRIE, PlAVIX was associated with a rate of gastrointestinal bleeding of
`2 0%, vs. 2.7% on aspirin. In CURE, the incidence of major gastrointestinal bleeding was 1.3%
`vs 0.7% (PlAVIX + aspirin vs placebo T aspirin, respectively). PLAVIX should be used with
`caulion in patients who have lesions With a propensity to bleed (such as ulcers). Drugs that
`might induce such lesions 5hould be used with caution in patients taking PlAVIX.
`Use in Hepatically Impaired Patients: Experience is limited in patients with severe hepatic
`disease, who may have bleeding diatheses. PlAVIX should be used with caution in this
`population.
`·
`·
`~
`Use in Renally-impaired Patients: Expe,ience 1s limited in patients with seveie renal
`impairment. PLAVIX should be used with caution in this population.
`Info rmation for Patients
`Patients should be told it may take them longer than usual to stop bleeding. that they may
`bruise and/or bleed more easily when lhey lake PI.AV!X or PLAVIX combined with aspirin,
`andthattheyshouldreportanyunusoalbleedingtotheirphysician Patientsshouldinform
`physicians and dentists !hat they are taking PLAVIX and/or any other product known to
`affect bleeding before any surgery is scheduled and before any new drug is taken.
`Droglnte,actions
`Study of specific drug inl"actions yielded the following results:
`Aspirin: Aspirin did not modify the dopidogrel-mediated inhibition of ADP-induced
`platelet aggregation. Concomitant administration ol 500 mg otasp1nn twice a day for 1 day
`did not signilicanlly increase the prolongation of bleeding time induced by PlAVIX. PLAVIX
`potenlialed lhe effect of aspirin on collagen-induced platelet aggregalion. PLAVIX and
`aspirin have been administered together for up to one year.
`Heparin: In a study in healthy volunteers, PLAVIX did not necessitate modification of the
`heparin dose or alter the effect of heparin on c'oagulat1on. Coadministration of heparin had
`no effect on inhibition of platelet aggregation induced by PlAVJX.
`Nonsteroidal Anti-Inflammatory Drugs (NSAIOs): In healthy volunleers receiving naproxen,
`concomitant administration of PLAVIX was associated with increased OCcult gastrointestinal
`blood loss. NSAIDs and PlAVIX should be coadministered with caution.
`Warfarin·. Bec.auseof the increased risk of tileeding, the concomitant administration of
`warfarin with PlAVJX should be undertaken with caution. (See PRECAUTIONs-General.)
`Other Concomitant Therapy: No clinically significant.pharmacodynamic interactions were
`obseived when PlAVIX was coadministered with atenolol, nifedipine, or both atenolol and
`n1fedipine.. The pharmacodynamicactivityof Pl.AVIXwas also not significantly influenced by
`the coadministration of phenobarbital, cimetidine or estrogen.
`The pharmacokinelics of digoxin or theophylline were nol modified by lhe coadminislralion
`of PlAVlX{clopidogrel bisulfate).
`At high concentrations in vitTO, clopidogrel inhibits P4so (2C9). Accordingly, PLAVIX may
`interfere with the melabolism of phenytoin, tamoxifen, tolbutamide, warfa,in,
`torsemide, fl uvastatin, and many non-steroidal anti•inflammatory agents, but there
`are no data with whtch to predict the magnitude of these interanions. eau1,on should be
`used when any of these drugs is coadministered with PLAVIX.
`·
`In addition to the above specific interaction studies. patients entered into clinical trials
`with PlAVIX received a variety of concomitant medications including diurelics, bela-blocking
`agents, angiotensin <onverting enzyme inhibitor,;, c.alcium an1agoniru, cholesterol
`lowering agents, coronary vasodilaton, antidiabetic agents {including insulin!, throm·
`bolytics, heparins (unfractionated and LMWH)' GPllb/llla antagonists, antiepileptic
`agents and hormone replacement therapy wi!hout evidence of cli11ically Jignificant
`adve~interactions.
`There are no dala on lhe concomitant use of oral anticoagulants, non-sludv oral anli•
`platelet drugs and chronic NSAIDs with clopidogrel.
`Drug/Laboratory Test Interactions
`Noneknowp.
`carcinogenesis, Mutagenuis, Impairment of Fertility
`There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks
`to mice and 104 weeks to rats at dosages up ton mg/kg per day, which afforded plasma
`exposures >25 times that in humans al the recommended daily dose of 75 mg.
`Clop:dogrel was not genotorlc in four in vitro tests (Ames lest, ONA•repair lest in rat hepato(cid:173)
`cytes, gene mutation assay in Chinese harmter fibroblasts. and melaphase chromosome analy(cid:173)
`sis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
`Clopidogrel was found to have no effect on fertility of male and female rats at oral doses
`up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis). ,
`Prtgnancy
`Pregnancy C.alegory B. Reproduction studies performed In rats and rabbits at doses up to
`500 and 300 mg/kg/day (respectively, 65 and 78 tilTles the recommended daily human dose
`on a mg/mZ basis), revealed no evidence of impaired f~rtility or feloloxicity due 10 clopido(cid:173)
`grel. There are, however, no adequate and well-con1rolled studies in pregnant women.
`Because animal reproduction studies are not always "predictive of a human response, PLAVIX
`shouldbeusedduringpregnancyonlyifclearlyn~ded.
`Nursing Mother$
`Studies in rats have shown thal clopidogrel and/or its metabolites are excreted in the milk.
`II is nol known whelher this drug is excreted in human milk. Because many drugs are excreted
`lnhumanmilkandbecauseofthepotentialforseriousadvellereactions innursinginlants,
`a decision should bemadewhethertodiscontinue nursingortodiscontinuethedrug, tak•
`ing into account the importance of the drug to the nursing woman.
`Pediatri<Use
`Safety and effectiveness in lhe pediatric population have not been established.
`Geriatric Use
`Of the tolal number of subjects in CAPRIE, CURE and ClARITY controlled clinical studies.
`approximalely ~ of patienls treated with PlAVlX were 65 vears of age and older and
`15" were 75 years and older. In COMMIT, approxrmately 58% of the patients treated with"
`PlAVIX were 60 years and older, 26% of whom were 70 yeall and older.
`The observed ris\:::of thrombotic events with clopidogrel plus aspirin versus placebo plus
`aspirin by age category is provided in Figures 3 and 6 for the CURE and COMMIT trials,
`respectively (see WNICAl STUDIES}. The observed risk of bleeding events wilh clopidogrel
`pl~aspirinve!lusplaceboplusaspirinbyagec.ategoryisprovidedinTables5and6forthe
`CURE and COMMIT trials, respectively (see ADVERSE REACTIONS)
`
`ADVERSE REACTIONS
`PLAVIX has been evaluated for safety in more than 42,000 patients, including over 9,000
`patients lreated for 1 year or more. The clinically important adverse events obseived in
`CAPRlE. CURE, CLARllY and COMMIT are discussed below.
`The overall toler.ib1lity of PlAVIX in CAPRIE was similar lo I hat of aspi1in regardless of age,
`gender and race, with an approxip,ately equal incidence (13%) of pa1ients withdrawing from
`treatmentbecauseofadve!lereactions.
`HemorrhagiC" In CAPRIE patients receiving PlAVIX. gastrointestinal hemorrhage occurred
`al a rate of 2.oot· and required hospitalization in 0.7%. In patients receiving aspirin, the
`corresponding rates were 2.7% and 1.1%, respectively. The incidence of intracramal hemor(cid:173)
`rhage was 0.4% for PLAVIX compared to 0.5% for aspirin.
`ln CURE, PLAVJX use with aspirin was associated with an increase in bleeding compared to
`placebo with aspirin (see Table 5) There was an excess in major bleeding in patients receiv(cid:173)
`ing PLAVIX plus aspirin compared w11h placebo plus aspirin, primarily gastrointestinal and
`al puncture sites. The incidence of intracranial hemorrhage (0.1'6}, and fatal bleeding
`(0.2%), were the same 1n both groups.
`The overall incidence of bleeding i's described in Table 5 for patients receiving both PLAVIX
`and aspirin in CURE.
`Table S: CURE Incidence of bleeding complicalions (" patients)
`PLAVIX
`Placebo
`(+ aspirin)*
`(+ aspirin)*
`(n=6259)
`(n=6303)
`3.7*
`2.7§
`2.2
`1.8
`0.2
`0.2
`0.9
`0.9
`0.7
`07
`0.1
`0.1
`o.s
`o.s
`1.2
`1.0
`1.6
`,:0
`0.4•
`0.3
`
`Event
`
`Majorbleedingf
`Life-threatening bleeding
`
`P-value
`
`0.001
`0.13
`
`0.00S
`
`:a;~l hem~globin drop
`Requiring surgical intervention
`Hemorrhagic strokes
`Requiringinotropes
`Requiringtransfusion(~units)
`Other major bleeding
`Significanllydisabling
`lntraocular bleeding wilh
`0.05
`significant loss of vision
`1.3
`Requiring 2·3 units of blood
`Minor bleeding 1
`5.1
`* Other standard therapies were used as appropriate.
`t Lifethreatenillgandothermajor bleeding.
`* Major bleeding evenl rate for PLAVIX + aspirin was dose-dependent on aspirin:
`<100 mg=2.6%; 100·200 mg= 3.5%; >200 mg= ◄ .9%
`Major bleeding event rales for PLAVIX + aspirin by age were: <f65 years= 2.5%, .?65 to
`<75 years= 4.1%, .?75 yea!l 5.9%
`§ Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin:
`<100 mg=2.09'; 100-200 mg= 2.39'; >200 mg=4.0%
`Major bleeding event rates for placebo T aspirin by age were: <65 years = 2.1% . .?65 to
`<75 years= 3.1%, .?75 years 3.6%
`1 ledtofnterruption of study medication.
`Ninety-two percent (9296) of the patients in the CURE study received hepann/U,1WH, and
`thirate of bleeding in these palients was similar to the overall resulls.
`There was no excess in major bleeds wi1hin seven days after coronary bypass graft surgery
`in patients who stopped therapy more than live days prior 10 surgery (event rate 4.4%
`PLAVIX + aspirin; 5.3% placebo+ aspirin). In patients who remained on therapy within five
`days of bypass graft surgery, the event rate was 9.6" for PlAVIX T aspirin, and 63% for
`placebo + aspirin.
`In ClARITY, the incidence ol major bleeding (defined as fntraaanial bleeding or bleeding
`associated with a' fall in hemoglobin> 5 g/dl) was similar between groups {1.3% versus 1.1%
`in the PlAVIX T aspirin and in the placebo + aspirin groups, respectively). This was consistent
`across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or
`heparin therapy. The incidence of fa1al bleeding (0.8% versus 0.6% m the PlAVIX + aspirin
`andin the placebo T aspirin groups, respectively) and intracranial hemorrhage (0.5%ve!lus
`0.7%, respectively) was low and similar in both groups.
`The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low
`and similar in both groups as sh~wn in Table 6 below.
`Table 6· Number (%1 of Patients with Bleeding Events in COMMlT
`Type of bleeding
`Pl.A.VIX
`Placebo
`P-value
`(+ aspirin)
`(+ aspirin)
`(N = 22961)
`(N=22JJ91)
`Major•noncerebralorcerebralblttding*"'
`134 (0.6lE)
`125(0.S~)
`0.59
`Majornoncerebral
`0.48
`82(0.4%)
`73(0.3%)
`Fatal
`36(0.2%)
`37(0.2%)
`0.90
`Hemorrhagic stroke
`55(0.2%)
`0.91
`56(0.2%)
`Fatal
`·41 (0.2%)
`39(0.2%)
`0.81
`Other noncerebral bleeding (non-mafor)
`831 (3.6%)
`721(3.1%)
`0.005
`Anynoncerebra l bleedi ng
`7n(3.4%)
`0.004
`896(3.9%)
`* MaJor bleeds are cerebral bleeds or non-cereDral bleeds thought to have caused death or
`!hat required lransfusion.
`.
`tt The relative rate of major noncerebral or cerebral bleeding was independent of age.
`Evept rates for PlAVIX + aspirin by age were: <60 years= 0.3%, ~60 to <70 yea!l = 0.'7",
`.?70 vears 0.8%. Event rates for placebo+ aspirin by age were: <60 years= 0.4", ~60 to
`<70 years= 0.6%, ~70 years 0.7%.
`Adverse events occurring in ~2.5" of patients on PLAV1X in the CAPRIE controlled clinical
`trial are shown below regardless of relationship to PLAVIX. The median duration of therapy
`was 20 months, with a maximum of 3 years.
`Table 7: Adverse Events Occurring in ~2.S" of PlAVIX Patients in CAPRIE
`" Incidence I'- Di~continuation)
`~
`Pl.A.VIX
`Aspirin
`[n=9599]
`[n=9586)
`
`0.03
`0.9
`2.4
`
`<0.001
`
`Body System
`Event
`Body as a Who/~-general dirorders
`· Ches! Pain
`Accidental/Inflicted ln1ury
`Influenza-like symptoms
`Pain
`Faligue
`CJrdioVilscular dirorders, general
`Edema
`Hypertension
`Central & peripheral nervous system disorders
`Headache
`Dizziness ·
`GastrointtStinal system disorders
`Any event
`Abdominal pain
`Dyspepsia
`Diarrhea
`Nausea
`Metabolic & nutritional disorders
`. Hypercholesterolemia
`Muscu/o-skeleta/-5ystem disorders
`Arthralgia
`Back Pain
`Plate lei, bleeding, & clotting d,rorde,s
`Purpura/